KR910005709B1 - Benzo thiazole derivative - Google Patents

Abstract

None.

Description

Benzothiazole derivatives

The present invention relates to benzothiazole derivatives showing excellent pharmacological action.

Asthma attacks occur as a result of a complex combination of biological responses. Asthma attacks are believed to be mainly due to airway narrowing caused by various chemical mediators produced and released by antigen antibody responses.

Examples of known chemical mediators are histamine, prostaglandins, SRS-A, and the like. Among them, SRS-A was proved to be leukotriene C ₄ and D ₄ by Dr. Samuelsson of Sweden in 1979. Since then, SRS-A has attracted attention because of its long-standing relationship between asthma attacks and SRS-A.

Furthermore, the release of leukotriene occurs in skin and nasal mucosal reactions, the inhalation of leukotriene causes asthma attacks, and the concentration of leukotriene increases significantly in the blood or bronchial alveolar lavage fluid (BACF) of patients with asthma attacks. It became. These facts suggest that leukotrienes are likely to be important mediators of asthma attacks.

Conventional anti-asthma drugs have been developed based on the conventional concept that the release of chemical mediators should be suppressed. Representative examples of such anti-asthmatic agents include the drops that have been sold since 1969. However, in conventional anti-cheat preparations including phosphorus, the median release inhibitor concentration in vitro differs from that in vivo. Moreover, much is unknown about the mechanism of action, and the development of anti-asthma drugs has been strongly desired.

In this situation, the present inventors have conducted extensive and intensive studies for a long time to develop a novel asthma treatment agent having a clinically excellent effect on the inhibition of leukotriene production due to the inhibition of 5-lymphoxy bran.

As a result, the present inventors have found that the above object is achieved by the following benzothiazole derivatives, and thus completed the present invention.

It is therefore an object of the present invention to provide novel benzothiazole derivatives and their pharmacologically acceptable salts which are effective as anti-asthmatic agents. It is another object of the present invention to provide a medicament comprising the above-mentioned compound or a pharmacologically acceptable salt thereof as an active ingredient.

The target compounds of the present invention are benzothiazole derivatives represented by the following general formula (I) and pharmacologically acceptable salts thereof. :

Wherein R ¹ , R ³ and R ⁴ may be the same or different and each is a hydrogen atom, a lower alkyl group, a halogen atom, an acyl group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a nitro group, an amino group, or a lower dialkylamino group. Two of R ¹ , R ³ , and R ⁴ may combine to form an aromatic ring composed of only carbon atoms or to which one nitrogen atom is added.

(식중 R⁷과 R⁸은 같거나 다르며 각각 수소원자 또는 저급알킬기이다.)으로 표현되는 기이며, R⁵및 R⁶는 같거나 다를 수 있고 각각R ² is a hydrogen atom, an acyl group,

(Wherein R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a lower alkyl group), and R ⁵ and R ⁶ may be the same or different and each

① hydrogen atom

② Expression

(식중 R⁹는 R¹⁰는 같거나 다를 수 있으며 각각 수소원자, 저급 알킬기, 할로겐 원자, 저급 알콕시기, 히드록시 저급알킬기, 또는 저급 디알킬기)으로 표현되는 기 또는 저급 알킬기.Wherein X is a group represented by the formula -CO- or a group represented by the formula -CH _2-

(Wherein R ⁹ is R ¹⁰ it may be the same or different are each a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxy lower alkyl group, or a di-lower alkyl) group or a lower alkyl group, which is represented by the.

③ Expression

(식중 R¹⁴및 R¹⁵는 같거나 다르며 수소원자 또는 저급알킬기)으로 표현되는 기), 식 -NH-SO₂-S¹⁶(식중R¹⁶은 저급 알킬기)으로 표현되는기, 또는 테트라조일기,A is a carbon atom or nitrogen atom X is a group represented by the formula -CO- or a group represented by the formula -CH ₂ -and R ¹¹ and R ¹² may be the same or different, respectively, hydrogen atom, halogen atom, carbamoyl group, -COOR ¹³ (wherein R ¹³ is a hydrogen atom or a lower alkyl group),

(Wherein R ¹⁴ and R ¹⁵ are the same or different and are represented by a hydrogen atom or a lower alkyl group), a group represented by the formula -NH-SO ₂ -S ¹⁶ (wherein R ¹⁶ is a lower alkyl group), or a tetrazoyl group,

④ Expression

Wherein X is a group represented by the formula -CO- or a group represented by the formula -CH ₂ -and R ¹⁷ is a hydrogen atom, a hydroxyl group or a lower alkyl group,

⑤ Formula -X- (CH ₂ ) _n -Z

(식중 R¹⁹및 R²⁰은 같거나 다르며 수소원자 또는 저급알킬기)으로 표현되는기, 식 -CONHR²¹(식중 R²¹은 수소원자, 저급알킬기 또는 시클로알킬기)으로 표현되는 기, 저급알콕시기, 시클로알킬기, 시아노기, 수신기.Wherein X is a group represented by the formula -CO- or a group represented by the formula -CH _2- , n is an integer of 0 to 10, Z is a formula -COOR ¹⁸ (wherein R ¹⁸ is a hydrogen atom or a lower alkyl group),

(Wherein R ¹⁹ and R ²⁰ are the same or different and are represented by a hydrogen atom or a lower alkyl group), a group represented by the formula -CONHR ²¹ (where R ²¹ is a hydrogen atom, a lower alkyl group or a cycloalkyl group), a lower alkoxy group, a cyclo Alkyl group, cyano group, receiver.

⑥ lower alkyl group

⑦ hydroxy lower alkyl group

⑧ Lower alkenyl group

⑨ Formula

(식중 R²⁷및 R²⁸은 같거나 다르며 수소원자 또는 저급알킬기)으로 표현되는 기, 또는

(식중 R²⁹및 R³⁰은 같거나 다르며 수소원자 또는 저급알킬기)으로 표현되는기, 또는Wherein A is a carbon atom or a nitrogen atom, R ²² , R ²³ , R ²⁴ are the same or different and hydrogen atom, lower alkyl group, lower alkoxy group, halogen atom, aminosulfonyl group, formula-(CH ₂ ) _a -COOR ²⁵ ( Wherein a is an integer of 0 to 6 and R ²⁵ is a group represented by a hydrogen atom or a lower alkyl group, formula -O- (CH ₂ ) _b -COOR ²⁶ (where b is an integer of 1 to 6 and R ²⁶ is a hydrogen atom) Or lower alkyl group)

Wherein R ²⁷ and R ²⁸ are the same or different and are represented by a hydrogen atom or a lower alkyl group, or

Wherein R ²⁹ and R ³⁰ are the same or different and are represented by a hydrogen atom or a lower alkyl group, or

⑩

(식중 R³²및 R³³은 같거나 다르며 수소원자 또는 저급알킬기)으로 표현되는 기, 또는 치환 또는 비치환된 페닐기, 또는R ³¹ is a lower alkyl group,

(Wherein R ³² and R ³³ are the same or different and represent a hydrogen atom or a lower alkyl group), or a substituted or unsubstituted phenyl group, or

⑪ R ⁵ and R ⁶ may be bonded together to form a ring which may contain nitrogen and oxygen atoms, and may be substituted or unsubstituted.

In the definition of the benzothiazole of the present invention, R ⁵ is hydrogen and R ⁶ is ②: R ⁵ and R ⁶ are hydrogen: R ⁵ is hydrogen and R ⁶ is ③: R ⁵ is hydrogen and R ⁶ is ⑨: R ⁵ and R ⁶ are ⑦: or the benzothiazole ring preferably has R ²⁰ at the 6 position.

Preferred compounds include the following.

6-hydroxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethyl-benzothiazole, 6-hydroxy-2- (4-carboxyphenylamino) -4,5,7- Trimethylbenzothiazole, 6-hydroxy-2-amino) -4,5,7-trimethylbenzothiazole, 6-hydroxy-2- (4-carboxyphenylamino) -5,7-diisopropylbenzo Thiazole, 6-hydroxy-2-CN, N-di (2-hydroxyethyl) amino) -5,7-diisopropylbenzothiazole, 6-hydroxy-2- (2-pyridylmethylamino ) -5,7-diisopropylbenzothiazole, 6-hydroxy-2- (4-sulfamoylbenzylamino) -5,7-dibromobenzothiazole and 4-hydroxy-2- (4- Sulfamoylbenzylamino) -5,7-dibromobenzothiazole.

The invention also relates to the production of leukotrienes due to the inhibition of 5-lymphoxygenase, including a clinically effective amount of the benzothiazole compound described above, and also a pharmacologically acceptable salt thereof, of the pharmacologically acceptable salt thereof. A pharmaceutical composition for inhibitory action and an anti-allergic agent comprising the benzothiazole compound described above or a pharmacologically acceptable salt thereof is provided.

The present invention also provides a method of treating a patient's disease caused by the production of leukotriene by administering a clinically effective amount of the above-described benzothiazole compound or a pharmacologically acceptable salt thereof.

In the compound (I) of the present invention, the term “lower alkyl group” used in the definitions of R ^1, R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁵ and R ⁶ of the above clauses 1 to ⑩ is 1 to 6 Straight or branched chain alkyl groups composed of carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1- Methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2 , 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, -1,1,2-trimethylpropyl, 1,2 , 2-trimethylpropyl, 1-ethyl-1-metalpropyl and 1-ethyl-2methylpropyl groups. Among them, methyl, ethyl, propyl, isopropyl groups and the like are preferable.

The term "lower alkoxy group" used in the definitions of R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 in} the above paragraphs ② to 의미 means a straight or branched chain alkoxy group composed of 1 to 6 carbon atoms, for example Is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tertiary pentyloxy, 1- Methyl butoxy, 2-methyl butoxy, 1,2-dimethylpropoxy, hexyloxy group and the like. Among them, methoxy, ethoxy group and the like are preferable.

The term “hydroxy lower alkyl group” used in the definitions of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is a hydroxy group linked to any of the carbon atoms of the lower alkyl group and lower alkyl group described above having 1 to 6 carbon atoms. Group, consisting of hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypro writing.

The term “halogen atom” used in the definitions of R ^9, R ¹⁰ , R ¹¹ , R ¹² , R ²² , R ²³ and R ^{24 in} the definitions of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is chlorine. , Cancelled, iodine and fluorine, among which chlorine and cancelled are preferred.

The term “acyl group” as used in the definitions of R ¹ , R ^2, R ³ , R ⁴ is intended to mean all acyl groups derived from aliphatic, aromatic and heterocycles. Preferred examples of the acyl group include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, vareryl, isovaleryl, and pivaloyl groups: aroyl groups such as benzoyl, toluoyl, and nattoyl: and Heteroaroyl groups, such as furoyl, nicothionyl, and isicotinoyl groups.

The term " lower dialkyl amino group " as used in the definitions of R ¹ , R ³ , R ⁴ , R ⁹ , and R ¹⁰ means a paid dialkylamino group derived from the lower alkyl group described above. An example of the most preferred lower dialkylamino group is a dimethylamino group.

R ^1, R ^3, R ⁴ defined in the "any of the R ^1, R ^3, R ⁴ two or even can form a ring by combining to add containing or a nitrogen atom of only carbon atoms" is The expression means that a benzene ring, a pyridine ring or a pyrimidine ring located in the 4th to 7th to 7th positions of the phenyl ring of the benzothiazole ring can be formed by the bonding of mutually adjacent carbon atoms.

Preferred examples thereof are as follows.

Wherein R ¹ , R ² , R ⁵ and R ⁶ are defined as above. The term "lower alkoxycarbonyl group" in the definition of R ² means a lower alkoxycarbonyl group derived from a lower alkoxy group as defined above consisting of 1 to 6 carbon atoms. Preferred examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and isobutoxycarbonyl groups.

The term “cycloalkyl group” in the definition of R ⁵ and R ⁶ in clause ⑤ means cyclopentyl, cyclohexyl group, and the like.

The term "lower alkenyl group" in the definition of R ⁵ and R ⁶ means a lower alkenyl group derived from a lower alkyl group consisting of 1 to 36 carbon atoms as defined above. Preferred examples thereof include 1-propenyl, 2-butenyl, 2-methyl-1-propenyl and 4-methyl-2-butenyl groups.

Preferred examples of the substituent for the substituted or unsubstituted phenyl group expression in the definition of R ³¹ in the above-mentioned provision of the definition of R ⁵ and R ⁶ include lower alkyl groups such as methyl groups, lower alkoxy groups such as methoxy groups, There is a carbamoyl group.

Concerning the definitions of R ⁵ and R ⁶ in Article VII: R ⁵ and R ⁶ may be combined together to form a ring which may additionally contain nitrogen and oxygen atoms and may be unsubstituted or substituted. Examples of the ring mentioned in the expression include pentagonal and hexagonal rings containing nitrogen or oxygen, such as morpholino, piperazinyl, pyrrolidinyl groups. Such rings may be unsubstituted or substituted. Substituents include lower alkyl groups composed of 1 to 6 carbon atoms such as methyl group and ethyl group, hydroxyl group, carbonyl group, and the group represented by the formula '= 0'. Among them, the following is very preferable.

Pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, sulphate, sulfate and phosphate: acetates, maleates, tartrates, organic acid salts such as methanesulfonate, benzenesulfonate and toluenesulfate: arginine and aspartic acid And amino acid salts such as glutamic acid. Moreover, such compounds of the present invention may take the form of metal salts such as sodium, potassium, calcium, and magnesium salts, and these metal salts are also within the range of pharmacologically acceptable salts. In addition, such compounds of the present invention may exist in hydrate form. The compounds of the present invention may be asymmetric carbon atoms when they carry certain substituents so that they may exist in the form of optical isomers. This is of course also included in the scope of the present invention.

Compound (I) of the present invention has a benzothiazole skeleton and has the following structure:

Wherein R ¹ , R ² , R ³ _, R ⁴ _, R ⁵ and R ⁶ are defined as above. In particular, compound (I) of the present invention has a benzothiazole skeleton and is substituted with various amino groups including a cyclic amino group in its 2-position. Furthermore, it is possible that the phenyl ring constituting the benzothiazole skeleton has up to four substituents. Most preferably, the group represented by the formula -OR ² in this connection is attached at the 6-position, and most preferably R ² is hydrogen.

으로 표현되는 여러가지 아미노기는 위와 같이 정의되며 아미노기의 바람직한 예는 식

(식중 X 및 Y는 위와 같이 정의)으로 표현되는 기, 식

(식중 X, A, R¹¹, R¹²는 위와 같이 정의)으로 표현되는 기, 식

(식중 X, R¹⁷은 위와 같이 정의)으로 표현되는 기, 식 -NH-X-(CH₂)_n-Z(식중 X, Z, n은 위와 같이 정의)으로 표현되는 기, 식

(식중 R³¹은 위와 같이 정의)으로 표현되는 기, 식

(식중 A, R²², R²³, R²⁴는 위와 같이 정의)으로 표현되는 기를 포함한다. 상술한 아미노기에서 X가 식 -CH₂-로 표현되는 기인 경우 바람직한 결과가 얻어질 수 있다.expression

The various amino groups represented by the above are defined as above, and a preferable example of the amino group is represented by the formula

(Where X and Y are defined as above)

(Where X, A, R ¹¹ and R ¹² are defined as above)

(Where X and R ¹⁷ are defined as above), and -NH-X- (CH ₂ ) _n -Z (where X, Z and n are defined as above)

(Wherein R ³¹ is defined as above)

(Wherein A, R ²² , R ²³ , and R ²⁴ are defined as above). Preferred results can be obtained when X is a group represented by the formula -CH ₂ -in the above-mentioned amino group.

(식중 Y는 위와 같이 정의)으로 표현되는 기이다. Y는 식

(식중, R⁹, R¹⁰은 위와 같이 정의)으로 표현되는 기인 것이 바람직하다.Among them, the most preferred amino group is

(Where Y is defined as above). Y is an expression

It is preferable that it is group represented by (wherein R <^9> , R <^10> is defined as above).

Therefore, the specific shape of the compound structure according to the present invention is that the phenyl ring of the benzothiazole skeleton bears a group represented by the formula -OR ² , and the 2-position of the benzothiazole skeleton is substituted with various amino groups. .

The compounds of the present invention are valuable as a variety of medicines based on leukotriene free inhibitors, in particular antiallergic and asthma therapies and prophylactic agents, with novel skeletons not found in traditional compounds showing this kind of pharmacological effect.

[Production process]

The compounds of the present invention can be prepared by various processes. Representative methods of preparing the mixtures of the present invention are mentioned below.

In the formula (I), when R ² is hydrogen, ie, any of the 4-, 5-, 6-, and 7-positions is a hydroxyl group, the hydroxyl group is protected in the form of methyl ether, the reaction is carried out, and the target substance is obtained. In the last step it is preferred to prepare the desired material by demethylation (ie according to the preparation method 8 mentioned below).

In the following preparation methods 1, 3, 5, 6 and 7, R ^{2 '} includes methyl groups as well as groups defined for R ² . When R ^{2 '} is a methyl group, the compound is not a target compound but a compound that can be used as a starting material anywhere in the preparation method.

[Manufacturing Method 1]

When R ⁵ and R ⁶ in formula (I) are hydrogen, the compounds of the present invention can be prepared, for example, in the following manner:

In particular, the compound represented by the general formula (II) is cyclized according to a conventional method for producing a compound represented by the general formula (III), which is one of the target compounds.

Compound (II) having an amino group in this reaction is cyclized using potassium thiocyanate and cancellation. For example, this reaction is carried out according to the method described in Beilstein, 27 (2), p.334. Examples of the reaction solvent include an acetic acid-water solution (acetic acid: water = 1: 1 to 95: 5).

The reaction temperature is generally in the range of 0 ° C to room temperature.

[Manufacturing Method 2]

When the target compound represented by general formula (I) is a compound represented by the following formula:

Such compounds can be prepared by the following cyclization reactions:

Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are defined as above.

In this method, compound (IV) was prepared from J. Org. In the presence of concentrated hydrochloric acid according to the method described in Chem., 35, 4103 (1970), 1,4 benzoquinone (V) was prepared by condensation with thiourea (VI).

Methanol, ethanol or the like is used as a solvent and the reaction temperature is in the range of 0 ° C to the reflux temperature of dissolution.

[Manufacturing Method 3]

Amidation by Acid Halide Method

(식중 J는 전술한 의미이거나 R³¹이 전술한 바와 같은 식 -SO₂-R³¹로 표현되는 기)에 의해 표현되는 경우, 본 발명의 화합물은 다음 과정에 의하여 제조될 수 있다.R ⁶ in formula (I)

(Wherein J is the aforementioned meaning or R ³¹ is a group represented by the formula -SO ₂ -R ³¹ as described above), the compounds of the present invention can be prepared by the following procedure.

Wherein R ¹ , R ^{2 ′} , R ³ , R ⁴ , R ⁵ and R ³¹ are defined as above and J is the same as defined in clauses 2 to ⑤ above on the definition of R ⁵ and R ⁶ . Is not without the group represented by the formula -X- and Hal is halogen.

In particular, the process involves the amidation reaction, i.e., the reaction of a compound having an amino group with an acid halide or with a acid, preferably in the presence of a base to produce an amide compound or It consists of.

Acidates and acid scavengers are used as acid halides. Examples of the base include carbonates of alkali metals such as sodium bicarbonate, potassium carbonate and sodium carbonate or alkali hydroxides such as hydrogen carbonate, sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine, pyridine and diethylaniline, and hydroxides. Sodium.

Appropriate solvents may be selected from solvents not involved in the present reaction.

[Manufacturing Method 4]

Amidation with Acid Anhydride

(식중 J는 전술한 의미와 같다)으로 표현되는 기이며 본 발명의 화합물은 다음 반응으로 제조될 수 있다.Formula (I) is R ⁶

Wherein J is the same as defined above and the compound of the present invention can be prepared by the following reaction.

In formula, R <^1> , R <^2>' , R <^3> , R <^4> , R <^5> and J are synonymous with the meaning mentioned above.

In this reaction, a compound (i) having an amino group is reacted with ethylchlorocarbonate, isobutyl chlorocarbonate or diethyl chlorophosphate to prepare a mixed acid anhydride, and the obtained acid anhydride is reacted with carboxylic acid (XII). To prepare an amide mixture (XIII).

Any base can be used. In addition, any solvent that does not participate in the reaction can be used. Examples of preferred solvents are tetrahydrofuran, N, N-dimethylformamide. The reaction temperature is preferably 0 ° C. in the mixed acid anhydride production step, and the range from 0 ° C. to the reflux temperature of the solvent is preferable in the next step.

[Manufacturing Method 5]

How to pass via seed base

으로 표현되는 기가 식 -NH-CH₂-JC식중 J는 전술한 의미와 갖는다)로 표현되는 기인 경우, 본 발명의 화합물은 다음 반응에 의해서도 제조될 수 있다 :Formula in general formula (I)

When the group represented by the formula -NH-CH ₂ -JC is a group represented by the formula (J has the above meaning), the compounds of the present invention can be prepared by the following reaction:

Wherein R ¹ , R ^{2 ′} , R ³ , R ⁴ and J have the same meanings as described above.

In the present reaction, a compound (XIV) having an amino group is reacted while removing aldehyde (XV) and water formed to prepare a seed base. In this case, any solvent that does not participate in the reaction can be used. Preferred solvents include benzene and toluene. The reaction temperature ranges from room temperature to solvent reflux temperature. Small amounts of ammonium acetate are added to speed up the reaction.

The obtained seed base (XVI) is then reduced to an amine compound (XV). Reducing agents used include lithium aluminum hydride, sodium borohydride, sodium cyano borohydride. It is also possible to carry out catalytic reduction in the presence of a catalyst consisting of palladium-carbon, platinum oxide, or rain nickel. Any solvent that does not participate in the reaction can be used. The reaction temperature is in the range from 0 ° C to the reflux temperature of the solvent.

Preferred solvents for this reaction include tetrahydrofuran and diethyl ether when sodium hydride is used: sodium borohydride or cyanoborohydride when methanol, ethanol, alcohol and water mixed solvents: for catalytic reduction Ethyl acetate, methanol, ethanol.

[Manufacturing Method 6]

Isobromide light oil production

Wherein R ¹ , R ^{2 ′} , R ³ , R ⁴ , R ⁵ and R ⁶ are defined as described above. Compound (XIV) having an amino group is diazotized according to the method described in Organic Synthesis, Collective Volume I, p. 135, and the formed diazonium salt is decomposed to prepare an imino bromo compound (VII). Examples of the diazotizing agent include sodium nitrite and hydrobromic acid.

Hydrochloric acid and copper are also used in the decomposition of diazonium salts. Any solvent that does not participate in the reaction may be used and may be used as hydrous acid or a solvent. The reaction temperature is in the range of 0 ° C to the reflux temperature of the solvent.

The iminobromo compound (X ') is reacted with an amine in the presence of a base to form a compound (VII). Any base may be used and any solvent that does not participate in the reaction may be used. The reaction can also proceed without solvent. The reaction temperature is in the range of 180 ° C. at room temperature.

[Manufacturing Method 7]

Reduction of amide compound into amine compound

When R ⁶ in the general formula (I) is a group represented by the formula -CH ₂ -J (J is defined as above), the compound of the present invention can be prepared by the following reaction.

Wherein R ¹ , R ^{2 ′} , R ³ , R ⁴ , R ⁵ and J are defined as above.

Amide (XIII) is reduced to an amine compound (XXI). Lithium aluminum hydride and diborane are used as reducing agents.

Solvents not involved in the reaction can be used as the reaction solvent. Preferred examples of the solvent include tetrahydrofuran, diethyl ether. The reaction temperature ranges from room temperature to solvent reflux temperature.

으로 표현되는 기(R⁷, R⁸은 위와 같이 정의된다)인 경우에는 디보란을 사용하며 R^2'이 다른 기인 경우에는 리튬 알루미늄 히드라이드를 사용한다.R ^{2 '} is an acyl group or formula

In the case of the group represented by R ⁷ and R ⁸ are defined as above, diborane is used, and when R ^{2 ′} is another group, lithium aluminum hydride is used.

[Manufacturing Method 8]

Demethylation

When R ² in formula (I) is hydrogen, the compound of the present invention can be prepared by the following method.

Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are defined as above.

The methyl compound (XXII) is demethylated to become a demethylated compound (XXIII). Demethylating agents include boron tribromide, trimethylsilyl iodide, and hydrogen / acrylic acid of acetic acid. Any solvent that does not participate in the reaction can be used. Methylene chloride, chloroform and the like are particularly preferred. The reaction temperature is in the range of 0 ° C to the reflux temperature of the solvent.

As described above, when R ² is hydrogen, the reaction is demethylated in the final step using a starting material consisting of a compound in which the hydroxyl group is protected in the form of methyl ether to obtain each desired compound.

Specific examples are given below to facilitate understanding.

Wherein R ¹ , R ³ , R ⁴ and Y are mentioned as above and Hal is a halogen atom.

The effect of the compound of the present invention will be mentioned in more detail in the following pharmacological experiments.

[Pharmacological Experimental Example]

Influence on the production of leukotriene C ₄ (LT) in lung sections of guinea pigs

Experimental Method

Anti-albumin guinea pig serum (1/10 dilution: 0.5 ml / 100 g) was intravenously injected into male Hartley guinea pigs (300-350 g) for passive sensitization.

After 16 to 18 hours of manual sensitization, Tyrode solution was circulated to remove blood and lungs were removed. The extracted lung was subdivided into 1 mm x 1 mm x 1 mm size under ice cooling. The pieces were washed and 150 mg of the pieces were suspended in 1.8 ml of the die rod solution and incubated at 37 ° C. for 5 minutes. A 3 μM test compound (compound of the invention) solution was added thereto and incubated for 10 minutes. Antigen solution (ofalbumin: final concentration of 10 μg / ml) was added thereto and incubated again for 15 minutes. The mixture was filtered through a nylon net. The amount of leukotriene C ₄ (LTC ₄ ) was measured by RzA kit in 100 μg of the filtrate.

[Experiment result]

The percent leukotriene C ₄ (LTC ₄ ) glass inhibition of each compound (indicated by the compound number used in the following example) is shown in Table 1.

The compound numbers of Table 1 correspond to the compound numbers of the examples.

TABLE 1

It is clear from the results of the pharmacological experiment that the present invention inhibits the production of leukotriene. Therefore, the compound of the present invention is useful as a medicine based on leukotriene production inhibitory action. The compounds of the invention are effective against allergies, in particular other diseases considered to be caused by asthma and leukotriene, namely psoriasis, skin diseases such as eczema, allergic rhinitis, and cardiovascular diseases.

In addition, various experiments by the present inventors confirmed that the present invention inhibits the production of leukotriene by inhibition of 5-lymphoxygenase and has an effect even when administered orally in the case of asthma. Therefore, the compound of the present invention is extremely valuable because it is particularly useful as a therapeutic agent and a prophylactic agent.

In addition, the compound of the present invention is useful in view of low toxicity and high safety.

In particular, in terms of safety, all the compounds of the present invention did not show major toxicity when administered once orally (300 mg / kg) in guinea pigs (heart: weight 300-350 g).

Therefore, the compound of the present invention is useful as a therapeutic composition for inhibiting leukotriene production due to 5-lymphoxygenase inhibition.

Specifically, the compounds of the present invention are useful as agents for the treatment and prevention of diseases considered to be caused by leukotriene, ie skin diseases such as psoriasis and eczema and allergic diseases such as allergic rhinitis and eczema. The compounds of the present invention are particularly useful as anti-asthmatic agents. The compounds of the present invention are prescribed in the form of tablets, powders, granule capsules, mixed syrups, and inhalants as agents for the treatment and prevention of such diseases. The dosage of the compound of the present invention will depend greatly on the symptoms, age, type of disease, and the like. Generally, about 0.1 to 1000 mg, preferably 1 to 500 mg, per adult is administered once to several times a day.

Pharmaceutical formulations are prepared from the compounds of the present invention using commercially acceptable carriers which are commercially available for pharmaceutical formulations.

In particular, when preparing oral solid preparations, the active ingredient is added with excipients and, if necessary, binders, disintegrating agents, lubricants, coloring agents, copulation agents, and the like, and then tablets, coating tablets, granules, powders, capsules, etc. are prepared. do.

Examples of excipients include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide. Examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, acacia, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl-methylcellulose, calcium citrate, dextrin and pectin Can be mentioned. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silky and hardened vegetable oils. Any coloring agent that is approved for addition to the pharmaceutical may be used. Examples of mating agents include cacao powder, menthol, aroma powder, menta powder, borneo and powdered cinnamon. Of course, sugar coatings, gelatin coatings and other coatings as appropriate may be applied to such tablets and granules.

When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, a solubilizer, and the like are added to the main component, and then an intramuscular injection or an intravenous injection is prepared according to a conventional method.

Embodiments of the present invention will be mentioned below. It goes without saying that the present invention is not limited thereto.

Although the following examples include starting materials, the target material has a compound number attached thereto.

In addition, the signal D ₂ O exchangeable with active hydrogen according to item shown in Table 2 to Table 12 H ¹ -NMR of is omitted.

Example 1

2-amino-6-methoxy-4,5,7-trimethylbenzothiazole

100 g of 1-amino-4-methoxy-2,3,5-trimethylbenzene was dissolved in 100 ml of acetic acid and 50 ml of water. 20 g of potassium thiocyanate was added to the solution at room temperature. The reaction mixture is cooled with ice and 37.5 ml of cancellation is added dropwise. The mixture was stirred for 30 minutes. The reaction solution was neutralized by addition of a 1N aqueous sodium hydroxide solution. The resulting insoluble material was filtered off and washed with water. The solid was recrystallized from methanol / tetrahydrofuran to give 123 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.16 (3H, s), 2.24 (3H, s), 2.35 (3H, s), 3.59 (3H, s)

Example 2

The same procedure as described in Example 1 was carried out to obtain the compound of Table 2.

TABLE 2

Example 3

2-amino-6-hydroxy-4,5,7-trimethylbenzothiazole

5 g of 2-amino-6-methoxy-4,5,7-trimethylbenzothiazole prepared in Example 1 are suspended in 100 ml of methylene chloride. 50 ml of methylene chloride solution (1M) of boron tribromide was added to the suspension and heated to reflux for 30 minutes. The reaction solution is poured into ice water and neutralized by adding an aqueous sodium bicarbonate solution. The fish crystals were separated by filtration and recrystallized in tetrahydrofuran / methanol to obtain 4.0 g of the title compound (white crystals).

m.p (℃): 268 ~ 272 (HCl)

¹ H-NMR (DMSO-d ₆ ) (HCl) δ: 2.16 (3H, s), 2.22 (3H, s), 2.32 (3H, s)

Example 4

The compound of Table 3 was prepared by performing the procedure of Example 3 in succession to the procedure of Example 1.

TABLE 3

Example 5

6-methoxy-2- (4-sulfamoylbenzamido) -4,5,7-trimethylbenzothiazole

68 g of 4-sulfamoylbenzoic acid were suspended in 500 ml of dimethoxyethane. 50 ml of thionyl chloride were added to the suspension and heated to reflux for 5 hours. Dimethoxyethane, thionyl chloride and hydrogen chloride were removed under reduced pressure. The residue was dissolved in 500 ml of tetrahydrofuran.

50 g of 2-amino-6-methoxy-4,5,7-trimethylbenzothiazole (synthesized from 1-amino-4-methoxy-2,3,5-trimethylbenzene by the method mentioned in Example 1); 100 ml of pyridine was added to the reaction solution, which was carried out under ice cooling. Then stirred at room temperature for 1 hour.

The reaction solution was poured into iced water and extracted with ethyl acetate under acidic conditions in which hydrochloric acid was present. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from methanol to obtain 41.4 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (3H, s), 2.38 (3H, s), 2.52 (3H, s), 3.63 (3H, s), 7.49 (2H, br, s), 7.89 (2H, d, J = 10Hz), 8.20 (2H, d, J = 10Hz), 12.83 (1H, br, s)

Example 6

6-methoxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethylbenzothiazole

38.7 g of lithium aluminum hydride was suspended in 1.2 l of tetrahydrofuran. Under stirring, 41.4 g of 6-methoxy-2- (4-sulfamoylbenzamido) -4,5,7-trimethylbenzothiazole was added to the suspension at room temperature. The reaction solution was heated to reflux for 40 minutes, and then the reaction solution was ice-cooled, and water was added thereto. The formed white precipitate was added to concentrated hydrochloric acid and dissolved. Aqueous solution of saturated sodium bicarbonate was added to adjust the pH to 4-5 and extracted with ethyl acetate.

The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was recrystallized from acetone / methanol to give 20.7 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 2.22 (3H, s), 2.34 (3H, s), 3.56 (3H, s), 4.58 (2H, d, J = 7) , 7.23 (2H, br, s), 7.42 (2H, d, J = 10), 7.72 (2H, d, J = 10), 8.32 (1H, br, t, J = 7)

Example 7

6-hydroxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethylbenzothiazole

20.7 g of 6-methoxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethylbenzothiazole was suspended in 500 ml of methylene chloride. 200 ml of methylene chloride solution (1 M) of boron triboromide was added to the suspension under stirring at room temperature and then heated to reflux for 30 minutes. The reaction solution was cooled, poured into saturated aqueous sodium hydrogen carbonate solution, neutralized and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting crystals were filtered to give 19.5 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.13 (3H, s), 2.20 (3H, s), 2.35 (3H, S), 4.57 (2H, d, J = 7Hz), 7.24 (2H, br, s), 7.50 (2H, d, J = 9 Hz), 7.74 (2H, d, j = 9 Hz), 8.84 (1 H, br, s), 8.14 (1 H, br, t, J = 7 Hz)

Example 8

6-hydroxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethylbenzothiazole hydrochloride

19.5 g of 6-hydroxy-2- (4-sulfamoylbenzylamino) -4,5,7-trimethylbenzothiazole was heated and dissolved in 2 l of tanol. Hydrogen chloride dissolved ethanol was added and then cooled. The formed crystals were separated by filtration to obtain 19.5 g of the title compound as a white crystal.

m.p. (° C.): 210 (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 2.15 (3H, s), 2.20 (3H, s), 2.38 (3H, s), 4.84 (2H, br, s), 7.56 (2H, d, J = 9 Hz), 7.78 (2H, d, J = 9 Hz)

Example 9

The compounds mentioned in Examples 1, 5, 6 and 7 were carried out sequentially to synthesize the compounds of Table 4.

TABLE 4a

TABLE 4b

TABLE 4c

Example 10

The compounds referred to in Examples 1, 5 and 7 were carried out sequentially to synthesize the compounds of Table 5.

TABLE 5

Example 11

2-methanesulfoamido-6-methoxy-4,5,7-trimethyl benzothiazole

1.0 g of 2-amino-6-APoxy-4,5,7-trimethylbenzothiazole prepared by the method of Example 1 was dissolved in 50 ml of tetrahydrofuran.

2.5 g of butoxide potassium was added for 30 minutes and stirred at room temperature for 30 minutes.

3.5 ml methanesulfonylchloride were added.

The reaction solution was stirred for 1 hour at room temperature.

The reaction solution was poured into iced water and extracted with ethyl acetate.

The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo.

The residue was purified by silica gel column chromatography to obtain 600 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 2.30 (6H, s), 3.40 (3H, s), 3.68 (3H, s)

Example 12

The compound of Table 6 was synthesized by following the procedure of Example 11 followed by the procedure of Example 7.

TABLE 6

Example 13

2-dimethylsulfoylamino-6-methoxy-4,5,7-trimethibezothiazole

1.0 g of 2-amino-6-methoxy-4,5,7-trimethyl-benzothiazole prepared in the same manner as in Example 1 was dissolved in 50 ml of tetrahydrofuran.

0.8 g of sodium hydride (55%) and 2 ml of dimethylsulfamoyl chloride were added to the reaction solution and heated to reflux for 1 hour.

The reaction solution was cooled at room temperature, poured into ice, and extracted with ethyl acetate.

The organic layer was washed with water and dried over anhydrous magnesium. The solvent was distilled off in vacuo.

The residue was purified by silica gel column chromatography to obtain 0.4 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.04 (3H, s), 2.14 (3H, s), 2.56 (3H, s), 2.91 (6H, s), 3.66 (3H, s)

Example 14

Example 7 was followed by the procedure of Example 13 to prepare the compound of Table 7.

TABLE 7

Example 15

2-acetamido-4-chloro-5,7-diisopropyl-6-methoxybenzothiazole

The procedure of Example 1 was followed by repeating the procedure of Example 5 to dissolve 2.0 g of 2-acetamido-5,7-diasopropyl-ethoxy-benzothiazole synthesized in 50 ml benzene.

1 ml of sulfuryl chloride was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was poured into iced water and extracted with ethyl acetate.

The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum.

The residue was purified by silica gel column chromatography to obtain 2.1 mg of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (6H, d, J = 7z), 1.50 (6H, d, J = 7H, z), 2.26 (3H, s), 3.78 (3H, s), 3.6 ~ 4.0 (2H, m)

Example 16

Compound No.76

2-amino-4-chloro-5,7-diasopropyl-6-hydroxybenzothiazole

50 ml of methanol was dissolved in 2.0 g of 2-acetamido-4-chloro-5,7-diisopropyl-6-methoxybenzothiazole prepared in the same manner as in Example 15.

6 ml of aqueous sodium hydroxide solution (5N) was added to the residue and heated to reflux for 1 hour.

The reaction solution was cooled, water was added, and extracted with ethyl acetate.

The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was suspended in 50 ml of methylene chloride and the procedure described in Example 7 was carried out to obtain 1.2 g of the title compound as a white compound.

m.p. (℃) 250 ~ 255 (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (6h, d, J = 7Hz), 1.34 (6H, d, J = 7Hz), 3.3 ~ 3.8 (2H, m)

Example 17

2-acetamido-5,7-diisopropyl-6-methoxy-4-benzothiazole

The procedure of Example 1 was repeated following the procedure of Example 1, and 3.0 g of 2-acetamido-5,7-diisopropyl-6-methoxy benzothiazole synthesized was dissolved in 50 ml of acetic acid. Concentrated 2 ml and a few drops of concentrated sulfuric acid were added to the reaction solution and stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography to obtain 2.1 g of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (6H, d, J = 8 Hz), 1.40 (6H, d, J = 8 Hz), 2.35 (3H, s), 3.2-3.8 (2H, m), 3.78 ( 3H, s)

Example 18

2-acetamido-4-amino-5,7-diisopropyl-6-methoxybenzothiazole

로

in

1.6 g of 2-acetamido-5,7-diisopropyl-6-methoxy-4-nitrobenzothiazole prepared in Example 17 was dissolved in 30 ml of methanol. A catalytic amount of palladium-carbon powder (10%) was added to the reaction solution and hydrogenated under 4 kg / cm 2. One hour after the start of the hydrogenation reaction, the palladium-carbon powder was filtered off, and methanol was removed under vacuum to obtain 1.3 g of the title compound as an oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (6H, d, J = 2 Hz), 1.45 (6H, d, J = 2 Hz), 2.23 (3H, s), 3.4-3.8 (2H, m), 3.37 ( 3H, s)

Example 19

Compound no. 77

2-amino-5,7-diisopropyl-4-dimethylamino-6-hydroxybenzothiazole

1.3 g of 2-acetamido-2-amino-5,7-diisopropyl-6-methoxybenzothiazole prepared in Example 18 was dissolved in 30 ml of atetonitrile. 0.4 g of sodium cyanoborohydride and 0.5 ml of aqueous formaldehyde solution (37%) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by acetic acid extraction. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was treated in the same manner as in Example 16 to obtain 0.9 g of the title compound as a white crystal.

m.p. (℃) 150 ~ 152

¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 2Hz), 1.48 (6H, d, J = 2Hz), 2.93 (6H, s), 3.2-4.2 (2H, m)

Example 20

Compound No.77

2-amino-4,6-dihydroxy-5,7-diisopropylbenzothiazole

4.1 g of 2-acetamido-4-amino-5,7-diisopropyl-6-methoxybenzothiazole prepared in Example 18 was dissolved in 20 ml of concentrated hydrochloric acid. 1.5 g of sodium nitrate was added to the reaction solution and stirred at room temperature for 30 minutes. 1 ml of concentrated sulfuric acid was added and stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate.

The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was treated in the same manner as in Example 16 to obtain 0.6 g of the title compound as white crystals.

¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (6H, d, J = 8Hz), 1.28 (6H, d, J = 8Hz), 3.3-3.6 (2H, m)

Example 21

5,7-dichloro-6-methoxy-2- (4-sulfamoylbenzylamino) benzothiazole

2.0 g of 5,7-dichloro-6-methoxy-2- (4-sulfamoylbenzamino) benzothiazole prepared by the method of Example 5 was dissolved in 50 ml of tetrahydrofuran. 15 ml of tetrahydrofuran solution (1M) of diborane was added to the reaction solution at room temperature and then heated to reflux for one hour. The reaction solution was cooled down. An aqueous ammonium chloride solution was added thereto and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography to obtain 0.7 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 3.82 (3H, s), 4.67 (2H, d, J = 6 Hz), 7.48 (1H, s), 7.52 (2H, d, J = 10 Hz), 7.82 ( 2H, d, J = 10Hz)

Example 22

In the same manner as in Example 21, the compound of Table 8 was prepared.

TABLE 8

Example 23

The compound of Table 9 was prepared by following the procedure of Example 7 in the procedure of Example 21.

TABLE 9

Example 24

6-methoxy-2- (2-oxopyrrolidino) -4,5,7-trimethyl-benzothiazole

0.36 g of 2- (3-ethoxy carbonyl propylamino) -6-methoxy-4,5,7-trimethylbenzothiazole prepared in the same manner as in Example 21, 5 ml of methanol 6 ml of tetrahydrofuran, 1 ml In water. 0.31 g of potassium hydroxide was added to the reaction solution, and stirred at 50 ° C for 30 minutes. The solvent was evacuated and 20 ml of benzene and 2 ml of thionyl chloride were added to the residue. The reaction was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under vacuum and the residue was purified by silica gel column chromatography to obtain 0.3 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.0-2.24 (2H, m), 2.30 (3H, s), 2.43 (3H, s), 2.56 (3H, s), 2.5-2.9 (2H, s), 3.68 (3H, s), 4.20 (2H, t, J = 7 Hz)

Example 25

Compound No.90

6-hydroxy-2- (2-oxopyrrolidino) -4,5,7-trimethylbenzothiazole

In the same manner as in Example 7, using 0.3 g of 6-methoxy-2- (2-oxopyrrolidino) -4,5,7-trimethylbenzothiazole prepared in Example 24 as a starting material, 0.2 g of the title compound was obtained.

m.p. (℃) 215-220

¹ H-NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 2.34 (3H, s), 2.50 (3H, s), 2.0-2.35 (2H, m), 2.7 (2H, m), 4.12 (2H, t, J = 6Hz)

Example 26

2- (3-cyclohexylcarbamoylpropylamino) -6-methoxy-4,5,7-trimethylbenzothiazole

2.1 g of 2- (3-ethoxy carbonylpropylamino) -6-methoxy-4,5,7-trimethylbenzothiazole prepared in the same manner as in Example 21 was dissolved in 6 ml of cyclohexylamine. The reaction solution was heated to 150 ° C. for 1 hour. Cyclohexylamine was distilled off and the residue was purified by column chromatography to give the title compound as an oil.

¹ H-NMR (CDCL ₃ ) δ: 0.8-2.2 (12H, m), 2.26 (3H, s), 2.34 (3H, s), 2.48 (3H, s), 2.2-2.9 (3H, m), 3.42 (2H, t, J = 6Hz), 3.70 (3H, s)

Example 27

Compound No.91

2- (3-cyclohexylcarbamoylpropylamino) -6-hydroxy-4,5,7-trimethylbenzothiazole

The title compound in the same manner as in Example 7 using 0.5 g of 2- (3-cyclohexylcarbaylpropylamino) -6-methoxy-4,5,7-trimethylbenzothiazole prepared in Example 26 as a starting material. 0.4g was obtained as white crystals.

m.p. (° C) 150 to 154

¹ H-NMR (DMSO-d ₆ ) δ: 1.0-2.1 (12H, m), 2.14 (3H, s), 2.20 (3H, s), 2.34 (3H, s), 2.1-2.5 (3H, m) , 3.44 (2H, t, J = 6 Hz)

Example 28

2-amino-6-hydroxy-4,5,7-trimethylbenzothiazole hydrochloride

2 g of thiourea was dissolved in 50 ml of ethanol. 1.8 ml of concentrated hydrochloric acid and 6.7 g of 2,3,6-trimethyl-1,4-benzoquinone were added to the reaction solution, followed by stirring at room temperature for 2 hours. The resulting crystals were separated by filtration and washed with acetonitrile to give 2.5 g of the title compound as white crystals. Prepared by the method mentioned in Chem, 35, 4103 (1970)]

m.p. (℃) 268 ~ 272 (decomposition)

¹ H-NMR (CMSO-d ₆ ) δ: 2.16 (3H, s), 2.22 (3H, s), 2.32 (3H, s)

Example 29

In the same manner as in Example 28, the compound of Table 10 was prepared.

TABLE 10a

TABLE 10b

Example 30

Compound No.111

2-amino-4-chloro-5-hydroxynaphtho [1,2-d] thiazole

Example 28 [J. 5 g of 2-amino-5-hydroxynaphtho [1,2-d] thiazole prepared from Org, Chem., 35 4103 (1970) was suspended in 50 ml of acetic acid. Chlorine gas was introduced into the suspension and stirred at room temperature for 10 minutes. The crystals contained in the reaction solution were separated by filtration, dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by silica gel chromatography to obtain 2.0 g of the title compound as white crystals. m.p. (℃)> 300

¹ H-NMR (DMSO-d ₆ ) δ: 7.22 (2H, s), 7.4-7.7 (2H, m), 8.2-8.4 (2H, m), 8.90 (1H, s)

Example 31

In the same manner as in Example 30, the following compound was prepared. Compound No. 112

2-amino-4-bromo-5-hydroxynaphtho [1,2-d] thiazole

m.p. (° C.); 〉 300

¹ H-NMR (DMSO-d ₆ ) δ: 7.10 (2H, s), 7.3-7.6 (2H, m), 8.0-8.3 (2H, m), 8.75 (1H, s)

Example 32

2-bromo-5,7-diisopropyl-6-methoxybenzothiazole

2-amino-5,7-diisopropyl-6-methoxybenzothiazole (1-amino-3,5-diisopropyl-6-meth according to the method mentioned in Beilstein 27 (2), p.334) 52 g (synthesized from oxy benzene) were dissolved in 700 ml of tetrahydrofuran.

58 ml of pickled acid (47%) was added to the reaction solution during ice cooling and 18 g of sodium nitrate was added. The reaction solution was refluxed for 1 hour and 2.5 g of powdered copper was added. The reaction solution was gradually heated and stirred at 50 ° C. for 1 hour. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by silica gel column chromatography to obtain 32 g of the title compound as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 7 Hz), 1.36 (6H, d, J = 7 Hz), 3.2-3.6 (2H, m), 3.72 (3H, s), 7.64 ( 1H, s)

Example 33

5,7-Diethylpropyl-2- (ethoxycarbonylphenylamino) -6-methoxy benzothiazole

32 g of 2-bromo-5,7-diisopropyl-6-methoxy benzothiazole prepared in Example 32 were mixed with 50 g of 4-ethoxycarbonylaniline.

The mixture was stirred at 100 ° C. for 30 minutes. The reaction solution was cooled to room temperature, and the solidified reaction product was dissolved in an ethyl acetate / tetrahydrofuran mixture and washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo and the residue was purified by silica gel chromatography to obtain 38 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7Hz), 1.36 (6H, d, J = 7Hz), 1.36 (3H, t, J = 8Hz), 3.2-3.6 (2H, m ), 3.70 (3H, s), 4.30 (2H, q, J = 8 Hz), 7.40 (1H, s), 7.50 (2H, d, J = 9 Hz), 7.98 (2H, d, J = 9 Hz)

Example 34

2- (4-carboxyphenylamino) -5,7-diisopropyl-6-methoxybenzothiazole

38 g of 5,7-diisopropyl-2- (4-ethoxycarbonyl) -6-methoxy benzothiazole prepared in Example 33 was dissolved in a mixed solution composed of 100 ml of methanol and 100 ml of tetrahydrofuran. 30 ml of 10N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled and neutralized with 2N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried to obtain 34 g of the title compound.

¹ H-NMR (CD ₃ OD) δ: 1.26 (6H, d, J = 7 Hz), 1.36 (6H, d, J = 7 Hz), 3.2-3.6 (2H, m), 3.72 (3H, s), 7.28 (1H, s), 7.66 (2H, d, J = 9 Hz), 7.94 (2H, d, J = 9 Hz)

Example 35

The compounds set forth in Table 11 were prepared by sequentially performing the procedures referred to in Examples 32, 33, 34 and 7, or the procedures referred to in Examples 32, 33 and 7.

TABLE 11

Example 36

2-benzylamino-6-hydroxy-4,5,7-trimethylbenzothiazole

5 g of 2-amino-6-methoxy-4,5,7-trimethylbenzothiazole were dissolved in 100 ml of benzene. 5.9 g of benzaldehyde and 3.5 g of ammonium acetate were added to the reaction solution, and water formed by a water recovery device was removed while heating under reflux for 5 hours.

The reaction solution was cooled to room temperature, washed with water and dried over anhydrous magnesium sulfate.

The solvent was then distilled off in vacuo. The entertains were dissolved in 100 ml of ethanol. 1.5 g of sodium borohydride was added to the reaction liquid while cooling the reaction solution with ice.

The reaction solution was stirred for 30 minutes. Ethanol was distilled off in vacuo and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo. The residue was treated in the same manner as in Example 7 to obtain 4.9 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.17 (3H, s), 2.20 (3H, s), 2.37 (3H, s), 4.76 (2H, s), 7.2-7.5 (5H, m)

Example 37

In the same manner as in Example 36, a compound of Table 12 was prepared.

TABLE 12

Claims (5)

Benzothiazole compounds of the formula and pharmacologically acceptable salts thereof:

Wherein R ¹ , R ³ , R ⁴ may be the same or different and are each a hydrogen atom, a lower alkyl group. A halogen atom, an acyl group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a nitro group, an amino group, or a lower dialkylamino group, and two of R ¹ , R ³ , and R ⁴ are composed of carbon atoms alone or in combination; To form an aromatic ring containing nitrogen atoms, R ² is a hydrogen atom, an acyl group,

(Wherein R ⁷ and R ⁸ are the same or different and each is a hydrogen atom or a lower alkyl group), R ⁵ is hydrogen and R ⁶ is a formula

Group represented by; Wherein Y is a C ₁ to C ₆ alkyl group or formula

Wherein R ⁹ and R ¹⁰ are each independently hydrogen, a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkyl group or a C ₁ to C ₆ alkoxy group. The benzothiazole compound and pharmacologically acceptable salt thereof according to claim 1, wherein R ² is hydrogen. The benzothiazole compound and pharmacologically acceptable salt thereof according to claim 1, wherein R ² is hydrogen, R ¹ , R ³ and R ⁴ are each methyl group and Y is —NH ₂ . A pharmacological composition comprising a clinically effective amount of a benzothiazole compound as defined in claim 1 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. A pharmacological composition for inhibiting leukotriene production due to 5-lipoxygenase inhibition consisting of a clinically effective amount of a benzothiazole compound or a pharmacologically acceptable salt thereof as defined in claim 1 and a pharmacologically acceptable carrier.